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MOLECULAR MISREADING IN
DROSOPHILA MELANOGASTER
by
Nicholas Hoe
_____________________________________
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
in Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(MOLECULAR BIOLOGY)
August 2007
Copyright 2007 Nicholas Hoe

Molecular Misreading (MM) is the inaccurate conversion of genomic information into aberrant proteins. For example, when RNA polymerase II transcribes a GAGAG motif it can sometimes create RNA with a two-base deletion. If this deletion occurs in a coding region, its translation can result in the production of misframed proteins. Certain misframed proteins increase in abundance during mammalian aging, and misframed versions of the human amyloid precursor protein (hApp) and Ubiquitin (hUbb) accumulate in neurodegenerative disease tissue. To determine if MM could be studied in Drosophila, cDNA clones encoding wild-type hApp and hUbb as well as frame-shifted versions (hUbb+1 and hApp+1) were expressed in transgenic flies using the doxycycline regulated tet-on system. Misframed proteins were abundantly produced in Drosophila, both from the transgenes and apparently from endogenous Drosophila Ubiquitin-encoding genes. Furthermore, the abundance of misframed proteins increased during aging. Overexpression of hUbb was toxic during male fly development, yet favored survival when expressed in male adults, while hUbb+1 did not have these effects. The data suggest that MM is an evolutionarily conserved aspect of gene expression and aging, with specific phenotypic consequences.

MOLECULAR MISREADING IN
DROSOPHILA MELANOGASTER
by
Nicholas Hoe
_____________________________________
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
in Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(MOLECULAR BIOLOGY)
August 2007
Copyright 2007 Nicholas Hoe